The present invention relates generally to DNA sequences encoding human thyroid hormone receptor proteins and more particularly to DNA sequences encoding human thyroid hormone receptor protein designated hTR.alpha.1, to the polypeptide products of recombinant expression of these DNA sequences, to peptides whose sequences are based on amino acid sequences deduced from these DNA sequences, to antibodies specific for such proteins and peptides, and to procedures for detection and quantification of such proteins and nucleic acids related thereto.
The physiological and developmental effects of thyroid hormone are mediated by a family of thyroid hormone receptors. The ligand-receptor complexes function as trans-acting transcriptional factors and exert their effects by binding to specific sequences in thyroid hormone responsive genes. (Larsen, P. R., et al., J. Biol. Chem., 261:14373-14376 (1986); Catanzaro, D. F., et al., Mol. Endocrinol., 1:90-96 (1987); Ye, Y. S., J. Biol. Chem., 262:6313-6317 (1986); Gustafson, T. A., et al., Proc. Nat'l. Acad. Sci. (USA), 84:3122-3126 (1987)). In humans, two different types of thyroid hormone receptors (TR) have been described. One, designated human TR.beta.(hTR.beta.), is encoded by a gene on chromosome 3 and is expressed in placenta and several cell lines. (Weinberger, C., et al., Nature, 324:641-648 (1986)). The second, designated human TR.alpha.2 (hTR.alpha.2), is encoded by a gene on chromosome 17 and is expressed in several tissues including kidney, testis, liver, and brain, as well as placenta (Benbrook, D., et al., Science, 238-788-791 (1987); Nakai, A., et al., Proc. Nat'l. Acad. Sci. USA, 85:2781-2785 (1988). cDNAs encoding other forms of thyroid hormone receptors have been isolated from a rat brain library (rTR.alpha.1) (Thompson, C. C., et al., Science, 237:1610-1614 (1987) and a chicken embryo library (cTR.alpha.). Sap, J., et al., Nature, 324:635-640 (1986).
Because of the possibility that additional forms of the thyroid hormone receptor might be expressed in human tissues, efforts have been directed towards isolating other putative receptors. The invention described herein relates, in part, to the results of these efforts.
Skeletal muscle is a thyroid hormone responsive tissue. Accordingly, a skeletal muscle cDNA library was screened for sequences that would cross-hybridize with the hTR.alpha.2 cDNA probe of the co-inventors herein. Nakai, A., et al., PNAS USA, 85:2781 (1988). A cDNA clone was isolated from this library and found to encode a unique form of the human thyroid hormone receptor that is closely related to the sequences of both hTR.alpha.2 and rTR.alpha.1. This third type of human thyroid hormone receptor, designated hTR.alpha.1, is expressed in many different tissues. Moreover, when expressed in vitro, a protein is produced which binds thyroid hormone with high affinity. A comparison of the sequences of hTR.alpha.1 and hTR.alpha.2 type thyroid hormone receptors suggests that they are likely encoded by the same gene and that alternative RNA splicing results in the synthesis of either hTR.alpha.1 or hTR.alpha.2.